Proliferation is known to be active generally in cancerous cells as compared with normal cells, and it is considered that the disordered proliferation due to an abnormality in the cell cycle control mechanism is the cause of cancer. A mitotic phase (M phase) of the cell cycle is the step of equally partitioning a chromosome into daughter cells, and a strict control in the process is essential for cell proliferation and survival. Therefore, it is believed that the inhibition of the M phase progression is an effective means for inhibiting cell proliferation, and practically, anticancer agents targeting M phase such as taxol, vincristine, or the like are achieving clinically effective results.
It has been known that many steps in the M phase progression are controlled by a protein kinase which phosphorylates proteins. A PLK (polo-like kinase) family is a serine-threonine kinase playing an important role in controlling the cell cycle including M phase, and this family includes four similar proteins of PLK1, PLK2, PLK3, and SAK (Nature Review Molecular Cell Biology (Nat. Rev. Mol. Cell Biol.), Vol. 5, 429, (2004)). Among them, PLK1 is known to participate in a plural of important stages at M phase in mammalian cells. That is, PLK1 has been reported to be participated in each step of entering the M phase, control of centrosomes, separation of chromosomes, and cytokinesis, by phosphorylating various substrates (Nature review Molecular Cell Biology (Nat. Rev. Mol. Cell Biol.), Vol. 5, 429, (2004)).
Moreover, there are many reports suggesting that PLK1 is overexpressed in various cancerous tissues in human. For example, PLK1 is acknowledged to be overexpressed in non-small-cell lung cancer (Oncogene, Vol. 14, 543, (1997)) and head and neck cancer (Cancer Research, Vol. 15, 2794, (1999)), and there are data showing that the overexpression of PLK1 is in relation with a prognosis of patients with those diseases. It is also reported that the expression of PLK1 is increased in other types of cancer such as in colon cancer, esophageal cancer, ovarian cancer, and melanoma. Such reports suggest that the overexpression of PLK1 is related to malignant alteration of cells in one way or another, and also that the function of PLK1 is important particularly in the progression of M phase in cancer cells.
From the facts, PLK1 is thought to be a possible target for anticancer approach. In fact, there are many reports on experiments for examining the inhibitory effect on the function of PLK1 against cancerous cells by using various experimental techniques. For example, from the experiment of expressing a function-inhibited PLK1 mutant in a cell by using a viral vector, it is reported that PLK1 inhibition promotes the cancerous cell-selective apoptosis (Cell growth & Differentiation, Vol. 11, 615, (2000)). There is also a report showing that PLK1 siRNA induces cancer cell growth inhibition and apoptosis (Journal of National Cancer Institute (J. Natl. Cancer Inst.), Vol. 94, 1863 (2002)). In addition, it is reported that PLK1 shRNA (Journal of National Cancer Institute (J. Natl. Cancer Inst.), Vol. 96, 862, (2004)), or antisense oligonucleotide (Oncogene, Vol. 21, 3162 (2002)) gives an antitumor effect in a mouse xenograft model. Those experimental results show that inhibition of the PLK1 activity causes promoting cancer cell growth inhibition and apoptosis, and strongly suggest that a PLK1 inhibitor may be an effective anticancer agent.
In the past, there are filed patent applications related to a compound having a PLK inhibitory effect (Pamphlet of International Publication Nos. 2004/043936, 2004/014899, etc.). However, there has not yet been reported a substituted imidazole derivative having an excellent PLK1 inhibitory effect.